Ibuprofen-containing medicament

ABSTRACT

An ibuprofen-containing medicament which contains ibuprofen only in the (S)-(+)-form is disclosed. (S)-(+)ibuprofen is more than twice as active as the racemate which has until now been used in the treatment of rheumatism. This permits reduction of the quantity of active ingredient and the size of the tablets or dragees.

This is a continuation of application Ser. No. 119,028, filed on Nov.10, 1987, now U.S. Pat. No. 4,877,620.

Non-steroidal anti-rheumatics (NSAR) are used to a great extent in thetreatment of rheumatism. Extensive results show that the NSAR areinhibitors of prostaglandin formation and that the therapeutic effect ofthe NSAR correlates with this inhibitory effect.

Alongside the required effects, i.e. anti-phlogistic, analgetic and insome cases antipyrretic properties, all NSAR have unwanted side effects.Among these are effects on the gastro-intestinal tract, stomach ulcerformation, diarrhea, sodium retention, oedema formation, and kidneydamage as well as effects on the central nervous system and respiratorytract. Besides these general side effects, specific unwanted sideeffects, especially allergies, can be caused by NSAR.

The NSAR, particularly those prescribed for rheumatic illnesses, must,in order to be effect and achieve the required relief for the patient,be administered in a sufficient dose. At high dosages which are oftenrequired to combat acute pain, and with a prolonged treat- ment which,especially with rheumatics, is often un- avoidable, the dangers of theunwanted side effects increase.

Ibuprofen, i.e. 2-(4-Isobutylphenyl)-propionic acid with the structuralformula is a tried and tested NSAR from the group of phenyl propionicacid derivatives that has shown itself to be effective in inhibitingprostaglandin synthesis in experiments with animals with inflammation.In therapy of humans, ibuprofen reduces pain, swelling and fever causedby inflammation. It shows the usual unwanted side effects of NSAR. Therecommended dosage range for oral and rectal administration lies, formaximum individual doses of 800 mg, between 1200 and a maximum of 2400mg ibuprofen per diem and is thus, in comparison to other NSAR,especially the tried and tested compounds Diclofenac and Indometacin,for which median daily doses of 0.2 or 0.1 g are recommended, relativelyhigh, the recommended median daily dose for ibuprofen being more than 1g. The individual dosage forms in tablets or dragees are correspondinglylarge and not less than 200 mg; as a rule they lie between 400 and 600mg since a sufficient quantity of the active ingredient is necessary toachieve the maximum plasma level. These large tablets or dragees areregarded as being a disadvantage since they are often hard to swallow.Smaller dosage forms which have to be taken more often or several at atime are not recommended because of the strain on the patient which thiscauses. The large dosage forms make a sustained-release formulation moredifficult as this requires inclusion of additional substances in thedosage form.

Ibuprofen has an asymmetric carbon atom and is present as the racematein the therapeutically-used form. It is known that for manypharmaceutically-active ingredients having one or more asymmetric carbonatoms that one enantiomeric form is often more effective or even muchmore effective than the other enantiomeric form; in isolated instancesthe pharmacological activity is accounted for by only one of theenantiomers. It is known that (R)-(-)-ibuprofen has substantially lesspharmacological activity than (S)-(+)-ibuprofen. Since, however, theineffective (R)-(-)-enantiomer is converted to the active(S)-(+)-enantiomer in vivo, as has been proved by analysis of ibuprofenmetabolites excreted in the urine, no therapeutic advantage has untilnow been expected from the use of the (S)-(+)-form instead of theracemate and a separation of the dextro rotatory form from the laevorotatory form has not been thought to be necessary.

It has now been found that, contrary to established opinion, accordingto which the ibuprofen-racemate was the most suitabletherapeutically-active form since the inactive (R)-(-)-enantiomer wasconverted into the active (S)-(+)-enantiomer in humans, that the(S)-(+)form of ibuprofen, i.e. in the absence of the (R)-(-)form has asubstantially greater pharmacological potential than was anticipated.The present invention is based on this recognition.

The invention relates to an ibuprofen-containing medicament and ischaracterized in that in the medicament ibuprofen is only present as the(S)-(+)-enantiomer. It was not to be expected that by the sole use ofthe (S)-(+)-enantiomer a substantial reduction of dosage would bepossible, since it was known that the as such largely inactive(R)-(-)-ibuprofen was converted into the active (S)-(+)-ibuprofen inhumans. It was, however, surprisingly found that the same analgeticactivity caused by a given dose of racemic ibuprofen can not only beachieved by half the dose of (S)-(+)-ibuprofen, but that even less thanhalf as much (S)-(+)-ibuprofen as racemic ibuprofen is required to givea given analgetic activity. This result is, on the basis of observationsuntil now on the mechanism of action of NSAR, particularly ibuprofen,extremely surprising. These findings originate from analgesia tests onmonkeys which, on the basis of their phylogenetic position, are mostsimilar to humans in their metabolic characteristics. These resultscould also be shown in humans.

This surprising result could be explained on the basis that the(S)-(+)-ibuprofen formed by inversion of the inactive (R)-(-)-form inhumans is, due to its formation in the liver and due to all other flowkinetics, quickly metabolically inactivated and excreted. Thus the(S)-(+)-form arising by metabolism from the (R)-(-)-form cannot arriveat the site at which its activity is required, i.e. the inflammedtissues, by the necessary distribution processes. On the other hand thepresence of the (R)-(-)-form can supress the transportation of the(S)-(+)-form to the inflammed tissue.

In order to achieve sufficient pharmacological effect in humans it is ofdecisive importance that pure (S)-(+)-enantiomer is used, since onlythen is a sufficiently high concentration in the blood achieved quicklyenough, this being necessary for quick distribution to the site ofaction. After administration of the (S)-(+)-form a substantially higherconcentration at the site of action is achieved than when the racemateor (R)-(-)-form is applied.

This is of substantial therapeutic significance since the reduction ofthe effective dose according to the invention also naturally reduces theunwanted side effects. The (R)-(-)-form which is practically in theracemate as ballast is left out along with the side effects caused bythis 50% portion of the racemate. In addition to this, the specificenzyme system (Co-A-derivative) required for the partial inversion ofthe (R)-(-)-form into the (S)-(+)-form occurring in the organism is nolonger required; it is not needed for the metabolism of the(S)-(+)-form. Since this enzyme system is essential for vital metabolicand detoxification processes, it is advantageous that it is no longerrequired on use of the (S)-(+)-form as sole ibuprofen active ingredientsince it thus remains completely available for the detoxification andmetabolic processes.

There is a reverse synergism here. (S)-(+)-ibuprofen shows, at half thedose, a greater activity than the corresponding racemate. Thus it ispossible to use a dosage form with less than half the quantity that wasuntil-now required to achieve a given result using the racemate. Theindividual dosage forms, i.e. tablets or dragees, etc., can be madecorrespondingly smaller. On the contrary, at the same size of tablet ordrageet twice the quantity of active ingredient can be formulated.Since, however, the inactive (R)-(-)-form, which until now had to be"carried" in the racemate not only caused a large volume of tablet ordragee to have to be maintained, but also competed with the(S)-(+)-enantiomer also present, the actual quantity of the activeingredient can be less than half the quantity of the racemate.

The 1200 to 2400 mg average daily dose thought necessary until now canat least be halved. The possible reduction of the dosage form also makessustained-release formulation possible which until now was difficult andnot carried out in practice. Two-stage tablets in which the(S)-(+)-enantiomer is present in sustained-release form in combinationwith non-sustained-release form may now also be more easily formulated;such dosage forms are no longer excessively voluminous and thusinapplicable for the patients.

The formulation of (S)-(+)-ibuprofen into tablets, dragees and otherformulations suitable for oral application is carried out in aconventional manner using known carriers and diluents. Such formulationsare known in galenism and can also be used in the present invention.This similarly applies for formulations for rectal administration. Allthe galenic preparations have the common feature, however, that, sincethey contain ibuprofen in the (S)-(+)-form only they are equallyeffective with a smaller quantity of the active ingredient, or, in theevent that they have the same concentration of active ingredient as theracemate form, then they have more than twice the pharmacologicalactivity of the racemate form.

For injectable preparations it is advantageous to formulate(S)-(+)-ibuprofen in combination with an amino acid. The solubilizationis improved in this way.

(S)-(+)-ibuprofen is obtained by a conventional optical resolution. Forexample, optically active phenyl ethyl amine can be used for thispurpose. (R)-(+)-phenyl ethyl ammonium-(R)-(-)-ibuprofemate and(S)-(-)-phenyl ethyl ammonium-(S)-(+)-ibuprofemate are less soluble thantheir diastereoisomers and can therefore be separated from these. Byrepeated recrystallization of the more difficultly solublediastereoisomers from an ethyl acetate/ethanol mixture, thediastereoisomers can be purified. By acid cleavage with, for examplehydrochloric acids and subsequent extraction with ether, thecorresponding ibuprofen enantiomer is obtained from thediastereoisomeric compound and produced in pure form.

Conventionally used adjuvants such as lactose, microcrystallinecellulose, powdered cellulose, maltodextrin or calcium hydrogenphosphate are suitable for the production of tablets, dragees and filmtablets; they are used in a quantity of 10 to 80%.

As tablet disintegrants can be used, for example, (in a concentration of2 to 8%) insoluble poly(1-vinyl-2-pyrrolidone), cross-linked sodiumcarboxymethyl cellulose, sodium carboxymethyl starch, formaldehydecasein, alginate and conventionally used starches.

As lubricant and separating agent there can be used metal soaps andtalcum in a concentration of ca. 1 to 5%.

As a further adjuvant, highly dispersed silicon dioxide can be used.

EXAMPLE 1

Ibuprofen, tablets

1 tablet contains in mg

    ______________________________________                                        (S)-(+)-ibuprofen*   300.0                                                    insoluble polyvinyl pyrrolidone                                                                    20.0                                                     microcrystalline cellulose                                                                         150.0                                                    magnesium stearate   10.0                                                     ______________________________________                                         *The active ingredient can be varied from 20 to 800 mg/tablet. The            adjuvants are correspondingly reduced or increased.                      

The tablets can also be produced as film tablets.

EXAMPLE 2

Ibuprofen, capsules

1 sustained-release capsule contains in mg

    ______________________________________                                        (S)-(+)-ibuprofen*     200.0                                                  (S)-(+)-ibuprofen* sustained-release                                                                 200.0                                                  ______________________________________                                         *The active ingredient in nonsustained-release form as well as in             sustainedrelease form does not have to be present in a 1:1 ratio; it can      also be used in the ratio 1:0.5-1:4. The quantities of adjuvants required     in these pellets vary in proportion to these changes in the amount of         active ingredient.                                                       

The sustained-release pellets of (S)-(+)-ibuprofen contain, in additionto the 200 mg of active ingredient saccharose corn starch stearic acidpoly(carboxymethyl) starch, sodium salt poly(1-vinyl-2-pyrrolidone)schellack talcum

EXAMPLE 3

Ibuprofen, suppositories

1 suppository contains in mg

    ______________________________________                                        (S)-(+)-ibuprofen*                                                                              450.0                                                       hard fat          1891.0                                                      Tocopherol        9.0                                                         ______________________________________                                         *In this preparation the amount of active ingredient can be varied from 2     to 800 mg; the necessary quantity of hard fat is correspondingly altered      to achieve a suppository of 2.3 g.                                       

EXAMPLE 4

Ibuprofen, injection solution

In a 3 ml capacity ampule 2 ml of solution having the followingcomposition are contained:

    ______________________________________                                        (S)-(+)-ibuprofen                                                                              300 mg                                                       dl-Lysine        212 mg                                                       ______________________________________                                    

EXAMPLE 5

Ibuprofen, injection solution

In an-ampule of 3 ml capacity are contained 2 ml of a solution havingthe following composition:

    ______________________________________                                        (S)-(+)-ibuprofen*                                                                              300.0 mg                                                    Meglumine         258.7 mg                                                    ______________________________________                                         *The quantity of active ingredient in these preparations can be varied        from 200 to 500 mg; the adjuvants lysine and meglumine must be reduced or     increased correspondingly. If necessary the quantity of the solvent,          water, must be increased or the size of the ampule must be varied. The pH     value of the injection solution should lie between 7.3 and 7.8.          

EXAMPLE 6

Conventionally used adjuvants can be used in the preparation of salves.

    ______________________________________                                        (S)-(+)-ibuprofen        5.0 g                                                *Neo-PCL self emulsifying W/O                                                                          25.0 g                                               Isopropyl myristate      7.0 g                                                Magnesium sulfate-heptahydrate                                                                         0.5 g                                                Phenylmercuryborate      0.004 g                                              ______________________________________                                         *Neo-PCL selfemulsifying W/O is a nonionic absorption base free of            paraffin oil and vaseline.                                               

(S)-(+)-ibuprofen is dissolved in a melt of Neo-PCL and isopropylmyristate at about 60° C.

Magnesium sulfate and the preservative are dissolved in water at 60° to70° C.

The water phase is stirred into the fat phase and the finished salvemixed until it has cooled to <30° C.

Synergistically working emulsifier combinations based on a mixture ofpurified oleic acid and a high potency lanolin alcohol fraction with 36%PCL-liquid and PCL-solid.

EXAMPLE 7

Hard gelatin capsules

(S)-(+)-ibuprofen is heated to 52° C. with polyethylene glycol 1500 in aratio of 1:1. The resulting clear melt is stirred and cooled to ca. 40°C. 600 mg of the still clear melt is then filled into hard gelatincapsules. The content of active ingredient in these capsules thusamounts to 300 mg (S)-(+)-ibuprofen.

The content of active ingredient can easily be controlled by decreasingor increasing the quantity of previously prepared melt which is added tothe hard gelatin capsule.

After the filling, the active ingredient-containing melt solidifies atabout 32° C. in the capsule. Sealing of the hard gelatin capsule is notnecessary. The capsules can be directly packed and stored.

Since the active ingredient in the capsules is a liquid at bodytemperature, the desired rapid resorption occurs which causes a rapidstart of activity. The required high level of (S)-(+)-ibuprofen isachieved within a short period.

Liberation of the active ingredient (S)-(+)-ibuprofen from such acapsule occurs significantly more quickly than from a correspondingcapsule which contains the same quantity of active ingredient but incrystalline form. Crystalline (S)-(+)-ibuprofen may, however, be dosedwithout adjuvants and without expensive processing. It is possible todose the pure substance as a melt (melting point 52° C.). In this case,however, the in vitro liberation of the active ingredient occurs onlysluggishly (retarded).

Evaluation of the Analgetic Activity of Ibuprofen

In this test the afferent nerves of the feet of female Rhesus monkeyswere electrically stimulated. For the test four adult female Rhesusmonkeys (macaca mulatta) were used.

The following active ingredients were used:

(S)-(+)-ibuprofen

(R)-(-)-ibprofen

(±)-ibuprofen

Acetylsalicylic acid

Methods

The monkeys were trained in such a way that they sat in chairs wearingan aluminium foil shoe during the test.

On the days when the test was carried out the monkeys were sat in thesestools. One foot of each monkey was smeared with electrode gel and thealuminium shoe was fitted over it.

A Grass-stimulator (S 88) was connected to the monkeys via amultiple-way switch (the positive lead was connected to the aluminiumshoe, the negative lead to the chair). An electrical stimulation, eachtime of 2 seconds duration with a frequency of 60 Hz was applied (themagnitude of stimulation was altered by adjusting the voltage suppliedto the stimulator; the corresponding current was measured by means of anammeter connected in series).

The stimulus required to achieve a stimulus threshold was determined.For this purpose the voltage was raised stepwise. The threshold voltagewas taken as the lowest voltage at which bending of the toes or twistingof the foot occurred.

Before application of the medicament the animals were allowed toacclimatize for at least one hour. During this period the thresholdvoltage was determined at 10 minute intervals until steady readings wereobtained.

Following the acclimatization period the carrier material or the activeingredient were orally administered. The threshold voltage required toeffect a stimulus response in the foot of each monkey was determined at30 minute intervals for 3 hours and then after 4 and 5 hours afteradministration of the active ingredient.

The observer and the stimulation apparatus were concealed behind aone-way mirror.

Each animal was treated with the following active ingredients in thegiven quantities:

    ______________________________________                                        1.     (S)-(+)-ibuprofen    50 mg/kg                                          2.     (R)-(-)-ibuprofen    50 mg/kg                                          3.     (±)-ibuprofen     50 mg/kg                                          4.     acetylsalicylic acid 100 mg/kg                                         5.     carrier (0.5% carboxymethyl                                                   cellulose                                                              ______________________________________                                    

Between the individual tests there was an interval of at least one week.

The active ingredients 1 to 4 were prepared for oral administration bysuspending them in 1.0% w/v Tragacanth. The medicaments were prepareddirectly before use and administered in a dose of 4 ml/kg.

The results obtained are shown in Table 1.

Carrier

Oral administration of the carrier (1.0% Tragacanth) gave a smalldecrease of the threshold voltage required to achieve a response.

Acetylsalicylic acid

After administration of 100 mg/kg acetylsalicylic acid the thresholdvoltage required for a stimulus response was increased by somethingapproaching 80%. This level of analgesia was achieved within 2 hoursafter administration of the active ingredient and remained above 60%throughout the duration of the test. Analgesia was assumed when thethreshold voltage was 20% above the level required after administrationof the carrier alone.

Ibuprofen

Oral administration of(R)-(-)-ibuprofen (50 mg/kg) gave no significantchange in the threshold voltage. In contrast thereto oral administrationof (S)-(+)-ibuprofen (50 mg/kg) gave an increase of the thresholdvoltage approaching 50%. This increase was achieved 90 minutes afteradministration and the threshold voltage remained elevated during therest of the test period. After administration of ibuprofen racemate (50mg/kg) the threshold voltage was increased by approximately 15%. Thisincrease was achieved within 90 minutes and the level remained duringthe rest of the test period. Although the racemate only increased thethreshold voltage by 15%, analgetic activity was assumed since thethreshold voltage decreased after administration of the carrier only.The difference between the median change between ibuprofen racemate andcarrier amounted to more than 20% for every time after 90 minutes withthe exception of 150 minutes.

Discussion of Results

In the test animals (S)-(+)-ibuprofen had a notable analgesic effectwhich was maintained for several hours. The (R)-(-)-isomer was inactiveand the racemate had a weak but long-lasting analgetic effect.

                                      TABLE 1                                     __________________________________________________________________________    Percentage change of the voltage required to achieve a                        stimulus response in the female Rhesus monkeys                                             Median percentage change in the threshold vol-                            Oral                                                                              tage at various times (h) after administration                            Dose                                                                              of the effective ingredient                                      Treatment                                                                              (mg/kg)                                                                            0,5 1,0 1,5 2,0 2,5 3,0 4,0 5,0                                 __________________________________________________________________________    Carrier  --   -6,6                                                                              -4,8                                                                              -13,0                                                                             -7,4                                                                              -4,3                                                                              -5,6                                                                              -11,5                                                                             -8,9                                                   *   *                                                      (+)-S-Ibuprofen                                                                        50   +9,5                                                                              +33,5                                                                             +51,2                                                                             +53,9                                                                             +45,5                                                                             +42,3                                                                             +33,7                                                                             +38,2                               (-)-R-Ibuprofen                                                                        50   -5,7                                                                              +4,0                                                                              +4,5                                                                              +0,5                                                                              -4,7                                                                              -7,0                                                                              -2,3                                                                              -3,4                                (+)-Ibuprofen                                                                          50   +6,4                                                                              +8,4                                                                              +15,7                                                                             +15,7                                                                             +8,5                                                                              +18,1                                                                             +9,7                                                                              +17,0                                                  *                                                          Acetylsalicylic                                                                        100  +35,8                                                                             +56,6                                                                             +41,4                                                                             +80,4                                                                             +74,6                                                                             +72,8                                                                             +66,1                                                                             +59,8                               Acid                                                                          __________________________________________________________________________     Statistical analyses carried out using the MannWhitney U Test                 *P < 0,05 compared to the carrier                                        

Percent change in the threshold voltage required to achieve a stimulusresponse in female rhesus monkeys which have been orally treated with(S)-(+)-ibuprofen, (R)-(-)-ibuprofen, (±)-ibuprofen, acetylsalicylicacid or with the carrier: ##STR1##

In a pilot run the human pharmaco kinetics of the ibuprofen forms wasinvestigated. The maximal plasma levels of the active (S)-(+)-form lie,after oral administration of the (S)-(+)-enantiomer on average 4 to 5times higher than after administration of the (R)-(-)enantiomer. Withinthe first 4 to 6 hours after application the areas under the plasmalevel curves (AUC) of the (S)-(+)-form after administration of the(S)-(+)-enantiomer are approximately a factor of 2.5 larger than afteradministration of the (R)-(-)-enantiomer. Only after this time periodare equally high or higher levels achieved after administration of the(R)-(-)-form than after administration of the (S)-(+)-form. Since theselevels are less than 10% of the maximum level they no longer contributeto the required activity.

Thus it can also be explained from a pharmaco kinetic point of view thatwithin the known period of action of ibuprofen (ca. 6 hours) no effectcan be expected from the (R)-(-)-form.

We claim:
 1. The method of eliciting an onset-hastened and enhancedanalgesic response in a human mammal suffering from pain and in need ofsuch treatment, comprising administering to such organism a dosageonset-hastening/enhancing analgesically effective amount of the S(+)ibuprofen enantiomer, and said enantiomer being free of its R(-)ibuprofen antipode.
 2. A pharmaceutical composition of matter adapted toelicit an onset-hastened and enhanced analgesic response in a mammalianorganism in need of such treatment, said composition comprising asolid-state dosage onset-hastening/enhancing analgesically effectiveamount of the S(+) ibuprofen enantiomer, said enantiomer being free ofits R(-) antipode, and a nontoxic pharmaceutically acceptable carrier ordiluent therefor.
 3. The pharmaceutical composition of matter accordingto claim 2, adapted for oral administration.
 4. The pharmaceuticalcomposition of matter according to claim 3, formulated as a tablet,caplet, pill or capsule.
 5. A method of achieving quick analgesia andgreater analgesic activity in a human experiencing pain comprisingadministering to such human a dosage amount of (S)(+)-ibuprofenenantiomer effective to achieve quick analgesia and greater analgesicactivity in such human, said enantiomer being in the absence of the(R)(-)-form.
 6. A pharmacological composition adapted to achieve quickanalgesia and greater analgesic activity in a human experiencing pain,said composition comprising a dosage of an amount of (S)(+)-ibuprofenenantiomer effective to achieve quick analgesia and greater analgesicactivity in such human, said enantiomer being in the absence of the(R)(-)-form, and a suitable carrier or diluent therefor.
 7. In anibuprofen-containing analgesic composition, the improvement in whichquick analgesia and greater analgesic activity in a human experiencingpain can be achieved wherein said ibuprofen present is the(S)(+)-enantiomer form which has been separated from its (R)(-)-form byconventional optical resolution.
 8. The composition of claim 7 whereinsaid conventional optical resolution comprises recrystallization andsubsequent purification of less soluble diastereoisomers.
 9. Apharmacological analgesic composition adapted to quickly achieve a highconcentration in the blood of a human experiencing pain uponadministration of said composition, said composition comprising a dosageamount of (S)(+)-ibuprofen enantiomer effective to quickly achieve ahigh concentration thereof in the blood of such human, said enantiomerhaving been separated from its (R)(-)-form by conventional opticalresolution.
 10. In a pharmacological composition suitable foradministration to humans experiencing pain containing an analgesicallyeffective dosage amount of ibuprofen, the improvement wherein saiddosage amount is reduced by at least half while retaining at leastcomparable analgesic activity, which improvement comprises using as thesole ibuprofen ingredient the (S)(+)-ibuprofen enantiomer.
 11. Themethod of claim 5 wherein said dosage amount of (S)(+)-ibuprofenenantiomer includes a suitable carrier or diluent therefor.
 12. In amethod of administering an ibuprofen-containing analgesic composition toa human experiencing pain, the improvement in which quick analgesia andgreater analgesic activity in such human can be achieved wherein saidibuprofen present is the (S)(+)-enantiomer form separated from its(R)(-)-form by conventional optical resolution.
 13. The method of claim12 wherein said conventional optical resolution comprisesrecrystallization and subsequent purification of less solublediasterioisomers.
 14. A method of administering a pharmacologicalcomposition adapted to quickly achieve a high concentration in the bloodof a human experiencing pain upon administration of said composition,said composition comprising a dosage amount of (S)(+)-ibuprofeneffective to quickly achieve a high concentration thereof in the bloodof such human, said enantiomer having been separated from its(R)(-)-form by conventional optical resolution.
 15. The method of claim14 wherein said conventional optical resolution comprisesrecrystallization and subsequent purification of less solublediasterioisomers.
 16. A method of achieving ibuprofen analgesia whileminimizing unwanted side effects as compared to administration of aracemic mixture of ibuprofen in a human experiencing pain, comprisingadministering to such human (S)(+)-ibuprofen free from the(R)(-)-enantiomer to achieve analgesia with a minimization of unwantedside effects from the presence of the (R)(-)-enantiomer.
 17. A method ofachieving analgesia in a human experiencing pain while minimizingunwanted side effects comprising administering to such human(S)(+)-ibuprofen free from the (R)(-)-enantiomer at a dosage level ofone half or less as compared with a dosage of racemic ibuprofen whichcomprises (S)(+)- and (R)(-)-ibuprofen to achieve comparable analgesiaeffect with less unwanted side effects.
 18. The method according toclaim 17 wherein the unwanted side effect is selected from the groupconsisting of gastro-intestinal tract effects, stomach ulcer formation,diarrhea, sodium retention, oedema formation, kidney damage, centralnervous system effects and respiratory tract effects.
 19. The method ofeliciting an onset-hastened and enhanced analgesic response in a humanmammal suffering from pain and in need of such treatment, comprisingadministering to such organism a dosage onset-hastening/enhancinganalgesically effective amount of the (S)(+) ibuprofen enantiomer, saidenantiomer being present in purified form sufficient to achieve saidresponse.
 20. A pharmaceutical composition of matter adapted to elicit aonset-hastened analgesic response in a mammalian organism in need ofsuch treatment, said composition comprising a solid-state dosageonset-hastening/enhancing analgesically effective amount of the (S)(+)ibuprofen enantiomer, said enantiomer being present in purified formsufficient to achieve said response, and a nontoxic pharmaceuticallyacceptable carrier or diluent therefor.
 21. A method of achieving theresponse of quick analgesia and greater analgesic activity in a humanexperiencing pain comprising administering to such human a dosage amountof (S)(+)-ibuprofen enantiomer effective to achieve quick analgesia andgreater analgesic activity in such human, said enantiomer being presentin purified form sufficient to achieve said response.
 22. Apharmacological composition adapted to achieve the response of quickanalgesia and greater analgesic activity in a human experiencing pain,said composition comprising a dosage of an amount of (S)(+)-ibuprofenenantiomer effective to achieve quick analgesia and greater analgesicactivity in such human, said enantiomer being present in purified formsufficient to achieve said response, and a suitable carrier or diluenttherefor.
 23. A pharmacological analgesic composition adapted to quicklyachieve the response of a high concentration in the blood of a humanexperiencing pain upon administration of said composition, saidcomposition comprising a dosage amount of (S)(+)-ibuprofen enantiomereffective to quickly achieve a high concentration thereof in the bloodof such human, said enantiomer being present in purified form sufficientto achieve said response.
 24. A method of administering apharmacological composition adapted to quickly achieve the response of ahigh concentration in the blood of a human experiencing pain uponadministration of said composition, said composition comprising a dosageamount of (S)(+)-ibuprofen effective to quickly achieve a highconcentration thereof in the blood of such human, said enantiomer beingpresent in purified form sufficient to achieve said response.